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Defining the pathogenesis of human inborn errors of immunity affecting the CARD11-BCL10-MALT1 complex

University of British Columbia

Primary immunodeficiency diseases or inborn errors of immunity are a group of rare genetic disorders in which key elements of the immune system are absent or dysfunctional. This typically manifests as greatly enhanced susceptibility to infection, autoimmunity, autoinflammation, malignancy, and/or atopy. Studying these patients can be very informative as they provide a rare opportunity to uncover the fundamental role of single genes in human immunity and disease, which can inform the development of targeted precision therapeutics and patient treatment. Germline mutations affecting caspase recruitment domain (CARD)—B cell CLL/lymphoma 10 (BCL10)—MALT1 paracaspase (MALT1) [CBM] complexes or ‘CBM-opathies’ have recently been linked to a broad spectrum of diseases, including invasive fungal disease, lymphoproliferation, severe atopic disease, psoriatic skin diseases, and profound combined immunodeficiency. These disorders can be difficult to diagnose as their (i) pathogenesis is incompletely understood; (ii) phenotypes are heterogeneous and can be similar to other PIDs; and (iii) incidence is low. With increased use of diagnostic next generation sequencing (NGS) in the clinic, a large number of variants of uncertain significance have been identified in these genes, further complicating diagnosis. The research presented in this thesis was focused on advancing the diagnosis, understanding, and treatment of germline CBM-opathies. We accomplished this by collecting and reporting all known clinical parameters from patients with germline mutations affecting CBM complexes and classified/unified these under the new term ‘CBM-opathies.’ Furthermore, we performed NGS on various patients with combined immunodeficiency, designed assays to functionally validate the pathogenicity of identified variants, and translated our findings into clinical care. Through this work, we were able to (i) classify the pathogenicity of four novel variations of CARD11; (ii) define the role of CARD11 in human B cell development, signalling, and function; (iii) and uncover the role of MALT1 paracaspase activity in mediating the pathogenesis of B cell Expansion with NF-кB and T cell Anergy (BENTA) disease.

Text

2023-10-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/76451

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/